title: Human papillomavirus type 16 E5 protein induces expression of beta interferon through interferon regulatory factor 1 in human keratinocytes.
abstract: Crucial steps in high-risk human papillomavirus (HR-HPV)-related carcinogenesis are the integration of HR-HPV into the host genome and loss of viral episomes. The mechanisms that promote cervical neoplastic progression are, however, not clearly understood. During HR-HPV infection, the HPV E5 protein is expressed in precancerous stages but not after viral integration. Given that it has been reported that loss of HPV16 episomes and cervical tumor progression are associated with increased expression of antiviral genes that are inducible by type I interferon (IFN), we asked whether E5, expressed in early phases of cervical carcinogenesis, affects IFN-β signaling. We show that the HPV type 16 (HPV16) E5 protein expression per se stimulates IFN-β expression. This stimulation is specifically mediated by the induction of interferon regulatory factor 1 (IRF-1) which, in turn, induces transcriptional activation of IRF-1-targeted interferon-stimulated genes (ISGs) as double-stranded RNA-dependent protein kinase R (PKR) and caspase 8. Our data show a new and unexpected role for HR-HPV E5 protein and indicate that HPV16 E5 may contribute to the mechanisms responsible for cervical carcinogenesis in part via stimulation of IFN-β and an IFN signature, with IRF-1 playing a pivotal role. HPV16 E5 and IRF-1 may thus serve as potential therapeutic targets in HPV-associated premalignant lesions.
authors.affiliation: Institute of Microbiology, University of Catanzaro Magna Graecia, Catanzaro, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Muto
authors.forename: Emilia
authors.initials: E
authors.lastname: Stellacci
authors.forename: Angelo Giuseppe
authors.initials: AG
authors.lastname: Lamberti
authors.forename: Edvige
authors.initials: E
authors.lastname: Perrotti
authors.forename: Aurora
authors.initials: A
authors.lastname: Carrabba
authors.forename: Giovanni
authors.initials: G
authors.lastname: Matera
authors.forename: Marco
authors.initials: M
authors.lastname: Sgarbanti
authors.forename: Angela
authors.initials: A
authors.lastname: Battistini
authors.forename: Maria Carla
authors.initials: MC
authors.lastname: Liberto
authors.forename: Alfredo
authors.initials: A
authors.lastname: Focà
mesh_terms: D002460:Cell Line; D054884:Host-Pathogen Interactions; D052162:Human papillomavirus 16 / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D016899:Interferon-beta / Q000096:biosynthesis*; D015603:Keratinocytes / Q000276:immunology* / Q000821:virology; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D000086082:Viroporin Proteins
chemical_list: D050856:Interferon Regulatory Factor-1; D016899:Interferon-beta; D009856:Oncogene Proteins, Viral; C494257:IRF1 protein, human; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins